Linn S C, Pinedo H M, van Ark-Otte J, van der Valk P, Hoekman K, Honkoop A H, Vermorken J B, Giaccone G
Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
Int J Cancer. 1997 May 29;71(5):787-95. doi: 10.1002/(sici)1097-0215(19970529)71:5<787::aid-ijc16>3.0.co;2-5.
Drug resistance plays an important role in chemotherapy failure in breast cancer. We studied the expression of MDR1, MRP, LRP, DNA topoisomerases, p53 and Ki-67 in different groups of breast cancer patients in relation to chemotherapy. Tissues from 6 normal breasts and 20 primary operable, 40 locally advanced and 10 anthracycline-resistant metastatic breast cancers were assessed. Sequential samples of the same patient were available from 17 patients with locally advanced breast cancer undergoing neo-adjuvant chemotherapy and in 7 metastatic patients undergoing paclitaxel treatment. Protein expression was investigated by immunohistochemistry. Significantly higher protein expression was observed for Pgp, Ki-67 and p53 in the locally advanced breast cancers than in primary operable breast cancers. No other significant differences in protein expression were found among the 3 breast cancer groups. Expression of none of the markers that could be assessed (Pgp, MRP, LRP, p53 and Ki-67) in locally advanced breast cancer had predictive value for pathological response. Interestingly, after chemotherapy a significant decrease in percentage of Ki-67 positive tumor cells was observed, whereas the other markers did not vary substantially. Furthermore, considering all breast cancer samples, a cumulative dose of doxorubicin >400 mg/m2 inversely correlated with Ki-67 positivity. However, 2 patients with a pathological complete remission had only 5-10% Ki67-positive tumor cells before chemotherapy, indicating that Ki67 negativity itself is not responsible for chemoresistance. In conclusion, none of the known proteins related to multidrug resistance predicted response to chemotherapy in breast cancer, and resistant clones left behind generally had a low proliferation rate.
耐药性在乳腺癌化疗失败中起着重要作用。我们研究了不同组乳腺癌患者中多药耐药蛋白1（MDR1）、多药耐药相关蛋白（MRP）、肺耐药蛋白（LRP）、DNA拓扑异构酶、p53和Ki-67的表达与化疗的关系。评估了来自6例正常乳腺组织以及20例原发性可手术、40例局部晚期和10例蒽环类耐药转移性乳腺癌组织。对于17例接受新辅助化疗的局部晚期乳腺癌患者和7例接受紫杉醇治疗的转移性患者，可获得同一患者的序贯样本。通过免疫组织化学研究蛋白表达。观察到局部晚期乳腺癌中P糖蛋白（Pgp）、Ki-67和p53的蛋白表达显著高于原发性可手术乳腺癌。在这3组乳腺癌之间未发现其他蛋白表达的显著差异。在局部晚期乳腺癌中，可评估的标志物（Pgp、MRP、LRP、p53和Ki-67）均无对病理反应的预测价值。有趣的是，化疗后观察到Ki-67阳性肿瘤细胞百分比显著下降，而其他标志物变化不大。此外，考虑所有乳腺癌样本，阿霉素累积剂量>400mg/m²与Ki-67阳性呈负相关。然而，2例病理完全缓解的患者在化疗前仅有5%-10%的Ki67阳性肿瘤细胞，这表明Ki67阴性本身并非化疗耐药的原因。总之，与多药耐药相关的已知蛋白均未预测乳腺癌对化疗的反应，残留的耐药克隆通常增殖率较低。
